Viral and Host Biomarkers of Human Rhinovirus Disease Severity in Transplantation

 描述(由申请者提供)：本建议描述了一个为期五年的研究培训计划，使我能够实现我的目标，成为一名独立的临床导向的学术研究人员，专注于免疫受损宿主中的呼吸道病毒感染。我的目标是通过更好地定义人类鼻病毒(HRV)和其他呼吸道病毒感染的不良结果的风险，并应用这些知识来开发疾病严重程度的生物标记物，来改善患者移植相关的传染病结果。这项建议建立在我在临床传染病、流行病学和生物统计学方法以及以实验室为基础的科学方面的培训基础上，并提供了一个详细的计划，以提高我在病毒学、免疫学和遗传学、进行前瞻性队列研究和基因表达统计分析方面的知识。这项建议融合了一群杰出导师的专业知识，其中包括传染病、流行病学、统计学和数据建模方面的专家，他们致力于确保这个项目的成功和我作为一名独立临床研究人员的职业发展。这项建议的第一个目标是分析决定HRV感染疾病严重程度的病毒因素。具体地说，我将确定血清和呼吸道样本中的病毒载量、病毒种类和病毒脱落对疾病结局的作用，包括进展为较低的肠道疾病和死亡率。这项建议的成功得益于独特的机会，可以对从大量患者队列中回顾和预期收集的样本进行统一的分子测试，从而有机会开发多变量模型并根据多个临床协变量进行调整。对于我的第二个目标，我将通过分析决定疾病严重程度的细胞因子谱和基因表达谱来确定宿主因素。再一次利用接触到大量的HCT接受者和建立的预期样本收集方案，我将能够开发出强大的生物标记物，这将为免疫受损宿主在HRV感染期间的生物途径提供重要的洞察。通过实现这项提案中的目标，我将大大有助于我们了解HRV感染在移植中的影响，以及我们使用病毒和宿主生物标记物预测疾病严重程度的能力。尽管移植实践有所改进，但HRV仍然是HCT受者感染性死亡的重要原因。生物标志物的识别有可能指导早期和特异的诊断工具，并将为制定预防和治疗策略提供基础。最终，该提案将使我能够开发一个更大的研究计划，以提高我们对免疫受损宿主中呼吸道病毒感染的理解和影响结果，然后将其应用于其他脆弱人群，包括婴儿、老年人和既有心脏或肺部疾病的个人。

 DESCRIPTION (provided by applicant): This proposal describes a five-year research training program that will allow me to achieve my goal of becoming an independent clinically-oriented academic researcher, focusing on respiratory viral infections in immunocompromised hosts. My goal is to improve patient transplant-related infectious disease outcomes through better defining risks for poor outcomes in human rhinovirus (HRV) and other respiratory viral infections, and applying this knowledge to develop biomarkers for disease severity. This proposal builds upon my training in clinical infectious diseases, epidemiologic and biostatistical methods and laboratory-based science, and provides a detailed plan to improve my knowledge of virology, immunology and genetics, conducting prospective cohort studies, and gene expression statistical analysis. This proposal incorporates the expertise of an outstanding group of mentors, including experts in infectious diseases, epidemiology, statistics, and data modeling, who are dedicated to ensuring the success of this project and the development of my career as an independent clinical researcher. The first aim of this proposal involves the analysis of viral factors that determine disease severity in HRV infection. Specifically, I will determine the role o viral load in serum and respiratory samples, viral species type, and viral shedding on disease outcomes including progression to lower tract disease and mortality. The success of this proposal is bolstered by the unique opportunity to perform uniform molecular testing on both retrospectively and prospectively collected specimens from a large cohort of patients, allowing the opportunity to develop multivariable models and adjust for multiple clinical covariates. For my second aim, I will identify host factors through the analysis of cytokine profiles and gene expression profiles that determine disease severity. Again utilizing access to a large cohort of HCT recipients and established prospective sample collection protocols, I will be able to develop robust biomarkers that will provide important insight into biologic pathways during HRV infection in immunocompromised hosts. Through accomplishing the aims in this proposal, I will contribute significantly to our knowledge of the impact of HRV infection in transplantation, and our ability to use viral and host biomarkers to predict disease severity. Despite improvements in transplant practices, HRV remains a significant cause of infectious mortality in HCT recipients. Identification of biomarkers has the potential to guide early and specific diagnostic tools and wil provide a basis to develop prevention and treatment strategies. Ultimately, the proposal will allow me to develop a larger research program to improve our understanding and affect outcomes of respiratory viral infections in immunocompromised hosts, which can then be applied to other vulnerable populations including infants, the elderly, and individuals with preexisting heart or pulmonary conditions.